p53 is widely known to have characteristic properties as follows. It is expressed and induced in response to stress etc. causing genetic toxicity. It activates the transcription of various genes. It brings about bioactivity such as cell cycle arrest, DNA repair, and apoptosis induction. The resent investigation on p53 revealed that the activation of transcription by p53 involves a histone acetyltransferase as the transcription coupling factor. The histone acetyltransferase acetylates the ε-amino group of the specific Lys residue in the histone N-terminus domain, thereby neutralizing positive charges. It is considered that acetylation of histone relaxes the nucleosome structure, thereby making the transcription factor to be recruited easily, which leads to the activated transcription. The histone acetyltransferase involving the activation of transcription by p53 is known to include p300, PCAF, PML, MOZ, etc. It has been reported that p300 acetylates p53 as well as histone, thereby enhancing the ability of p53 to bind to a specific DNA. (Avantaggiati M L. et al., Cell 89:1175-1184 (1997), Lill N L. et al., Nature 387:823-827 (1997)) It has turned out that p300 have CH1 and CH3 domains rich in cysteine/histidine and Q-rich domain rich in glutamine and any one of these domains binds to the N-terminal transcription activating domain.
It has also been reported that PCAF, in conjunction with p300, functions as the coactivator of p53. (Scolnick, D. M. et al., Cancer Res., 57:3693-3696 (1997)) JMY, in conjunction with p300, functions as the coactivator of p53, thereby activating Bax gene which induces apoptosis. (Shinkama, N. et al., Mol. Cell, 4:365-376 (1999)) As mentioned above, it has turned that p300 is a coupling factor essential for p53 to express its function. It has also turned out that p300 functions not only as the transcription coactivator for p53 but also as the coactivator of various transcription factors, such as p73 (p53 family), CREB, AML1, Myb, NF-κB, STAT, C/EBP, IRF3, and MyoD.
On the other hand, just as mutation of p53 gene is observed in a cancer patient, so mutation of p300 is observed in a cancer patient. The shedding of p300 gene due to translocation of chromosome is observed in a patient of acute myelogenous leukemia. (Kitabayashi, I. et al., Leukemia, 15:89-94 (2001), Chaffanet, M. et al., Genes Chromosomes Cancer, 28:138-144 (2000), Ida, K. et al., Blood, 90:4699-4704 (1997), Satake, N. et al., Genes Chromosomes Cancer, 20:60-63 (1997), Taki, T. et al., Blood, 89:3945-3950 (1997), Sobulo, O. M. et al., Proc. Natl. Acad. Sci. USA, 94:8732-8737 (1997), Borrow, J. et al., Nature Genet., 14:33-41 (1996), Panagopoulos, I. et al., Hum. Mol. Genet., 10:395-404 (2001)) There is another report concerning mutation of p300 gene in solid cancer such as large bowel cancer and breast cancer. (Gayther, S. A. et al., Nature Genet., 24:300-303 (2000)) Moreover, p300 is a target of oncogene product of an oncogenic virus. Adenovirus E1A, SV40T antigen, papilloma virus E6, and Tax of HTLV bind to p300 to inhibit its function. It is conjectured that the mutation of p300 gene and the binding of p300 to oncogene product prevent p53 as a coactivator from activating transcription for p300 and this is the cause of transformation.
As mentioned above, the histone acetyltransferase p300 plays an important role for p53 to express bioactivity. It has been suggested that transformation would be induced if the function of p300 is inhibited. Therefore, development of an inhibitor will be useful for analyzing the function and action of p300. It is also expected that it will be useful for elucidation of transformation involving p300 if it is known whether or not there exists p300 inhibitor in a living organism although mutation of p300 gene has been observed in cancer patients.